The project aims to explore why inheritance of the E4 variant of apolipoprotein E (ApoE4) is a significant risk factor for onset and progression of AD. The rationale for this proposal is driven by several observations: 1) that inheritance of the ApoE4 variant is a very strong risk factor for AD relative to inheritance of ApoE3, 2) that manifestations of altered brain morphology and function are apparent in ApoE4 individuals, early in life, decades before plaques and tangles are apparent, and 3) that inheritance of ApoE4 is a risk factor for several diseases suggesting a general deficit in pathways affecting neuroprotection, repair, cell survival etc. We anticipate that altered pathways impacted by ApoE of relevance to AD can be identified by a comparison of gene profiles between vulnerable cell populations of ApoE variants. Our second speculation is that while it is clear that ApoE4 affects the accumulation of amyloid-beta (A2) due to its effects on clearance, there are pathways mediated by ApoE receptor family signaling that could also provide a secondary point of vulnerability. This is demonstrated by the observation that inheritance of ApoE4 is a risk factor for other diseases or events that involve brain injury, and that the altered morphology of neurons of ApoE4 individuals suggests less capacity to respond favorably to injury. The combination of a poor overall response to insult, coupled with selective vulnerability of cell types that rely heavily on ApoE mediated pathways could explain why inheritance of ApoE4 variant is more of a problem for AD than other neurodegenerative diseases. The project aims to identify pathways at risk in both humans and a mouse model with different ApoE variants. We anticipate that these studies will generate new ideas about the etiology of AD in this large population group that might suggest novel preventative or therapeutic measures. PUBLIC HEALTH RELEVANCE: ApoE4 carriers are at significantly heightened risk of AD but clinical trials are becoming increasingly stratified to exclude ApoE4 carriers. As it is possible to test for ApoE genotype very early in life, it is imperative to identify pathways that increase risk as it may be possible to intervene therapeutically from an early age. RNA profiling vulnerable cell populations from pathologically normal ApoE4 carriers is expected to identify novel pathways at risk, allowing for biomarker and therapeutic developments. Performing identical experiments on ApoE targeted mice will provide corrolatory data, as well as generating novel information on this valuable mouse model of an important AD risk factor.